The human immune system is critical to protect against infection with pathogenic microorganisms. However, inappropriate immune responses against our own tissues or non-harmful environmental triggers such as beneficial commensal bacteria that surround us can promote autoimmune or chronic inflammatory diseases. Indeed, emerging studies in patients and murine model systems indicate that abnormal host-commensal relationships are either associated with or causally linked to numerous chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Genetic association and epidemiologic studies suggest that IBD is associated with dysregulated innate and adaptive immune responses that promote dysregulated host- commensal interactions and commensal bacteria-driven chronic intestinal inflammation. Recent studies have highlighted a role for innate lymphoid cells (ILCs) and their effector cytokine IL-22 in regulating intestinal inflammation. In new preliminary studies, I identified that ILCs are critical for maintenance of selective host- commensal relationships by anatomically-restricting a defined subset of commensal bacteria to the gut associated lymphoid tissues (GALT) of healthy mammals. This selective regulation could occur via two mechanisms; first, an innate pathway of IL-22 cytokine production limited peripheral dissemination of GALT- resident commensal bacteria to prevent systemic inflammation. Second, ILCs directly regulated adaptive immune responses and maintained normal host immune responses to GALT-resident commensal bacteria to prevent intestinal inflammation. Finally, I also observed the presence of ILCs in intestinal samples from healthy human donors, and dysregulated host-commensal relationships to the same defined subset of GALT- resident commensal bacteria in IBD patients. I will employ these powerful basic and translational approaches to delineate the pathways that regulate host-commensal relationships and maintain intestinal homeostasis in the context of human health and IBD. Three specific aims of this project will determine (i) the innate mechanism by which ILCs regulate selective host-commensal relationships to maintain systemic immune cell homeostasis, (ii) mechanisms by which ILCs regulate host adaptive immune responses and maintain host- commensal relationships to prevent intestinal inflammation, and (i) whether the pathways regulating innate and adaptive host-commensal relationships are dysregulated and associated with disease severity in human IBD. Collectively, these studies will systematically interrogate the role and mechanisms by which ILCs maintain normal host-commensal relationships in basic mouse models and pioneer translational studies examining these pathways in human patients. I anticipate that defining the mechanistic contributions of ILCs to regulating selective host-commensal relationships could identify novel targets and direct the development of future preventative and therapeutic strategies to IBD and multiple other chronic human inflammatory diseases. PUBLIC HEALTH RELEVANCE: Inflammatory bowel disease (IBD) is a multifactorial disease that represents a major public health challenge and economic burden. The goals of this application are to interrogate the pathways by which a recently recognized innate cell population termed innate lymphoid cells (ILCs) regulates normal host-commensal bacteria relationships to maintain a state of health and prevent chronic intestinal inflammation. Delineating the complex pathways that limit inflammation in response to intestinal commensal bacteria will expand our understanding of the pathogenesis of IBD and help direct the development of future preventative and therapeutic strategies.